Summary Our overall objective is to provide an atomic-level understanding of ligand binding and plasticity in HIV gp120 as it pertains to processes of cell entry by HIV and opportunities for its intervention. We plan to continue our structural studies on HIV gp120 in the context of our consortium of P50 Program Project activities. Our technical focus is on both x-ray crystallography and on cryogenic electron microscopy (cryo-EM), so as to determine structures at sufficient resolution to develop mechanistic insights; however, associated computations, binding experiments and assays of conformational dynamics also will be pursued. We use structure to optimize candidate inhibitors as chemical probes of function and potentially for use as therapeutic agents, we use crystal binding screens of chemical fragments from which new lead compounds might be developed, and we use structural analysis of discrete envelope states to study conformational transitions and gp120 plasticity. We build not only on our recent experience in this project, but also on our earlier structural investigations of CD4, HIV gp120s, and associated antibodies. We have adopted or developed both appropriate expression systems for making the required proteins and also appropriate assays for following inhibitory action. We interact with all other elements of the program project: most intimately with Project 3 on chemistry (Smith), Project 2 on virology (Sodroski), and Project 4 on small molecule peptidomimetics (Chaiken), and importantly with Project 1 on dynamics by single-molecule FRET (Mothes), and with both core A on computation (Abrams) and core B on cellular mechanism (Finzi). 18